Inadequate Blood Glucose Control Is Associated With In-Hospital Mortality and Morbidity in Diabetic and Nondiabetic Patients Undergoing Cardiac Surgery

Our study demonstrates that inadequate blood glucose control (BGC) after cardiac surgery is not specific to patients with diabetes mellitus (DM). Inadequate BGC, regardless of DM status, was independently associated with in-hospital mortality and morbidity. Our findings have epidemiological, clinical, academic, and financial implications. We suggest that DM patients represent only a fraction of those suffering derangement of glucose metabolism after surgery. The projected future number of adults with DM is an underestimate of the number likely to be affected by deranged glucose metabolism and its related complications. Inadequate BGC after surgery seems to represent a separate clinical entity that is explained only partially by undiagnosed and diet-controlled diabetes. Our data suggest that strict protocols to maintain BGC should be used for all patients. However, the efficacy of these protocols and the pathophysiologic mechanisms of this condition need further research. In addition, further research and guidelines as to how best to manage these patients are needed. Currently, important clinical decisions such as choice of screening test, strategy for maintaining adequate BGC, and the ideal target level of BGC are often left to the individual clinician. This has resulted in inconsistencies in the definition of undiagnosed DM, stress hyperglycemia, and inadequate BGC; marked variation in estimates of prevalence; and significant variation in treatment, the impact of which remains uncertain. Our findings also may apply to patients admitted for major noncardiac surgery. The impact on life expectancy and on hospital resources is potentially enormous. See p 113.

Prediction of First Events of Coronary Heart Disease and Stroke With Consideration of Adiposity

The key determinants of cardiovascular disease (CVD) are age, sex, cholesterol, high-density lipoprotein cholesterol, systolic blood pressure level, cigarette smoking, and diabetes mellitus. Greater adiposity generally has not been associated with the development of CVD when the traditional variables mentioned above are used to predict outcome. Data from 24 years of follow-up for the Framingham Offspring Study population sample were used to estimate the effect of body mass index (BMI) on risk of CVD. In a simple prediction model of CVD that included age, sex, and smoking, a 1-SD unit (4.33 kg/m2) of BMI imparted a 28% effect on risk of initial CVD events. After full adjustment with the traditional CVD prediction factors, the effect of an SD of BMI remained statistically significant but declined to 10%. It was estimated that 67% of the BMI effects appear to operate through the ratio of cholesterol to high-density lipoprotein cholesterol, systolic blood pressure, and diabetes mellitus. These results imply that a considerable portion of the adverse effects of BMI are exerted through traditional metabolic risk factors and that long-term follow-up of middle-aged adults was required to fully identify these effects. See p 124.

As an alternative mode of therapy for patients with symptomatic obstructive hypertrophic cardiomyopathy, alcohol septal ablation has emerged and is increasingly being performed in centers worldwide. However, there continue to be questions about the efficacy of septal ablation, particularly when compared with septal myectomy. In this study, which was performed at a single tertiary hypertrophic cardiomyopathy referral center, the overall survival after either septal ablation or myectomy was similar. Septal ablation was associated with a higher rate of acute complications. Survival free of severe symptoms also was comparable in the overall population, but patients ≤65 years of age had a lower rate of persistent or recurrent symptoms if they had myectomy. Septal ablation is an efficacious procedure if performed in an experienced institution and may improve symptoms in a subset of patients with obstructive hypertrophic cardiomyopathy. However, the in-hospital complication rate is higher with septal ablation and symptom relief is better with myectomy, especially in younger patients. These findings should be considered when the choice of septal reduction therapy is offered to hypertrophic cardiomyopathy patients. Long-term follow-up is required to determine the ultimate role of ablation in the treatment algorithm of these patients with hypertrophic cardiomyopathy. See p 131.

In Vivo Monitoring of Inflammation After Cardiac and Cerebral Ischemia by Fluorine Magnetic Resonance Imaging

Currently, neither a clinically useful method to assess local inflammatory processes associated with the risk of plaque rupture nor a robust imaging method that provides information about local activity of inflammation (which plays a crucial role in various cardiovascular disease states such as ischemia/reperfusion, myocarditis, transplant rejection, or stroke) is available. In the present study, we demonstrate in murine models of myocardial and cerebral ischemia that nanoemulsions of perfluorocarbons can be used to precisely visualize localized inflammatory processes as hot spots by simultaneous acquisition of morphologically matching proton (1H) and fluorine (19F) magnetic resonance images. Injected perfluorocarbons are phagocytized primarily by monocytes/macrophages, resulting in 19F magnetic resonance imaging intensity signals along the border of infarcted areas as a result of progressive infiltration of the labeled immunocompetent cells. Because of the lack of any 19F background in the body, observed signals are robust and exhibit an excellent degree of specificity. Perfluorocarbons are biologically inert and have been shown to be nontoxic in humans. Thus, 19F MRI has the potential to be clinically applicable as a new diagnostic modality not only for acute but also for chronic inflammatory processes such as plaques in atherosclerosis. See p 140.

Numerous studies have shown that immune cells including macrophages play crucial roles in the development of organ rejection. The ability to monitor the migration and localization of specific cell types in vivo, noninvasively, and in real time will greatly improve our understanding of the complex roles that different cells play in cardiac allograft rejection. This study presents the feasibility of imaging individual recipient macrophages in vivo by magnetic resonance imaging over long periods of time in a rodent heterotopic working-heart transplantation model with the use of a sensitive contrast agent, micrometer-sized paramagnetic iron oxide particles. In this study, recipient cells, mainly macrophages, have been labeled in vivo by direct intravenous administration of micrometer-sized paramagnetic iron oxide particles before heart transplantation. This cell-labeling procedure is convenient for clinical application. Thus, this approach provides a novel methodology for studying the mechanisms of cardiac allograft rejection in both animals and humans. Moreover, the current gold standard for diagnosing and staging rejection after organ transplantation is biopsy, which is not only invasive but also prone to sampling errors because rejection sites are highly heterogeneous. The activated macrophages have been found to be the primary cells in the cellular infiltrate of rejecting grafts. Thus, this imaging modality using magnetic resonance imaging to monitor cell migration in real time, with whole-heart visualization of cellular infiltration, could potentially lead to a powerful clinical tool, providing information for noninvasive evaluation of graft rejection, managing treatment, and predicting outcomes after heart transplantation. See p 149.

Specific Jagged-1 Signal From Bone Marrow Microenvironment Is Required for Endothelial Progenitor Cell Development for Neovascularization

Although accumulating evidence has indicated that therapy with endothelial progenitor cells (EPCs) could be a promising modality for vascular regeneration, the problems of quantity and quality control need to be resolved to achieve translational application in humans. Pathological conditions such as aging, diabetes mellitus, and hypercholesterolemia lead to a decrease in circulating EPCs and impairment of their proliferative and migratory function. These limitations may be solved by the integration of both in vitro expansion and quality control of EPCs by genetic modification, such as transducing vascular endothelial growth factor, glycogen synthase kinase-1β, human telomerase reverse transcriptase expression, or adjunctive cytokines that promote EPC mobilization. The promise of our therapeutic strategy is that governed Notch signaling in culture can produce the preferred quality and quantity of EPCs needed to enhance vasculogenic potential. The manipulation of Jag-1 ligand–mediated signals in culture before transplantation would allow EPCs to increase in number and augment their vasculogenic potential in patients with ischemic diseases. See p 157.

Hypoxia-Inducible Factor-1 Is Central to Cardioprotection: A New Paradigm for Ischemic Preconditioning

During the past decade, very exciting research efforts have revealed a central role of hypoxia-inducible factor (HIF) in mammalian oxygen homeostasis. In addition to its role in increasing erythropoietin production in response to limited oxygen availability, many other adaptive responses to hypoxia were found to be regulated by HIF, including metabolic adaptation, vascular angiogenesis, and attenuation of inflammatory hypoxia. In the present studies, we explored the hypothesis that HIF-1 also is central to ischemic preconditioning of the heart. Our results provide pharmacological and genetic evidence for a central role of HIF-1 in myocardial adaptive processes elicited by ischemic preconditioning. These studies also suggest pharmacological strategies to activate HIF in the treatment of myocardial ischemia. The use of prolylhydroxylase inhibitors appears to be a particularly promising pharmacological approach. However, many questions remain about the use of HIF activators. For example, the potential consequences of HIF activation on the risk of de novo or recurrent neoplastic diseases have to be thoroughly addressed before clinical use in humans. HIF activators also are associated with dramatic increases in hematocrit and circulating red cell volume, which may carry the risk of acute thromboembolic complications. Nevertheless, HIF activators, particularly the prolylhydroxylase inhibitors, represent a group of novel therapeutic agents that have great therapeutic potential in the treatment of conditions characterized by the acute need of tissues to adapt to hypoxia such as that which occurs during inflammatory bowel disease, stroke, renal ischemia, or myocardial infarction. Thus, these compounds could cover a very wide range of clinical applications. See p 166.